A high-fat diet is associated with the development of obesity seen in experimental animals and, in all likelihood, plays a role in the epidemic of obesity seen in affluent nations. The long term objectives of this research proposal are to understand the mechanisms which underlie the development of obesity in rats eating a high-fat diet and to develop strategies to prevent this form of obesity. This research project has focused on two strains of rats, one of which develops obesity when eating a high-fat diet, called SENSITIVE rats and a second strain which is RESISTANT to developing obesity while eating the same high-fat diet. This difference in response to a high-fat diet implies that the mechanisms controlling energy balance differ between these two strains and suggests that through manipulation of these mechanisms, energy balance might be altered. The clinical implications of such a finding are manifest. The general hypothesis of this proposal is that switching from a low to a high-fat diet activates signals in the RESISTANT rats which are integrated in the brain to maintain energy balance by reducing food intake and/or by increasing energy expenditure. The overall approach is based on the concept that energy balance is a regulated system with afferent feed-back signals about the state of nutrient stores and a central integrating system for translating messages into efferent signals which regulate food intake and energy expenditure. The hypothesis that the effects of 3-hydroxybutyrate act as an afferent signal will be tested by manipulating hepatic portal levels. The central integration of information connected with the switch from a low- to a high-fat diet will be examined by lesioning separate hypothalamic nuclei and by recording the ambient local concentration of the neurotransmitters serotonin and norepineplirine. The final set of studies will examine the effect of infusing beta-agonists into the central nervous system or peripherally to test the hypothesis that activation of central or peripheral adrenergic receptors might prevent the development of obesity in rats eating a high-fat diet.